Table_9_Comprehensive Profiling of Gene Expression in the Cerebral Cortex and Striatum of BTBRTF/ArtRbrc Mice Compared to C57BL/6J Mice.XLSX

Mouse line BTBR T+ Iptr3tf/J (hereafter referred as to BTBR/J) is a mouse strain that shows lower sociability compared to the C57BL/6J mouse strain (B6) and thus is often utilized as a model for autism spectrum disorder (ASD). In this study, we utilized another subline, BTBRTF/ArtRbrc (hereafter referred as to BTBR/R), and analyzed the associated brain transcriptome compared to B6 mice using microarray analysis, quantitative RT-PCR analysis, various bioinformatics analyses, and in situ hybridization. We focused on the cerebral cortex and the striatum, both of which are thought to be brain circuits associated with ASD symptoms. The transcriptome profiling identified 1,280 differentially expressed genes (DEGs; 974 downregulated and 306 upregulated genes, including 498 non-coding RNAs [ncRNAs]) in BTBR/R mice compared to B6 mice. Among these DEGs, 53 genes were consistent with ASD-related genes already established. Gene Ontology (GO) enrichment analysis highlighted 78 annotations (GO terms) including DNA/chromatin regulation, transcriptional/translational regulation, intercellular signaling, metabolism, immune signaling, and neurotransmitter/synaptic transmission-related terms. RNA interaction analysis revealed novel RNA–RNA networks, including 227 ASD-related genes. Weighted correlation network analysis highlighted 10 enriched modules including DNA/chromatin regulation, neurotransmitter/synaptic transmission, and transcriptional/translational regulation. Finally, the behavioral analyses showed that, compared to B6 mice, BTBR/R mice have mild but significant deficits in social novelty recognition and repetitive behavior. In addition, the BTBR/R data were comprehensively compared with those reported in the previous studies of human subjects with ASD as well as ASD animal models, including BTBR/J mice. Our results allow us to propose potentially important genes, ncRNAs, and RNA interactions. Analysis of the altered brain transcriptome data of the BTBR/R and BTBR/J sublines can contribute to the understanding of the genetic underpinnings of autism susceptibility.

小鼠品系BTBR T+ Iptr3tf/J（以下简称BTBR/J）相较于C57BL/6J小鼠品系（B6）表现出较低的社会互动性，因此常被用作自闭症谱系障碍（ASD）的模型。在本研究中，我们采用了另一个亚系，即BTBRTF/ArtRbrc（以下简称BTBR/R），并通过微阵列分析、定量RT-PCR分析、多种生物信息学分析和原位杂交技术，对BTBR/R小鼠与B6小鼠的关联脑转录组进行了分析。我们重点关注大脑皮层和纹状体，这两者均被认为是与ASD症状相关的脑回路。转录组分析识别出在BTBR/R小鼠与B6小鼠之间差异表达的基因（DEGs；包括974个下调和306个上调的基因，以及498个非编码RNA [ncRNAs]）。在这些DEGs中，有53个基因与已确立的自闭症相关基因相一致。基因本体（GO）富集分析突出了包括DNA/染色质调控、转录/翻译调控、细胞间信号传导、代谢、免疫信号传导以及神经递质/突触传递相关术语在内的78个注释（GO术语）。RNA相互作用分析揭示了新的RNA-RNA网络，包括227个与ASD相关的基因。加权相关网络分析突出了包括DNA/染色质调控、神经递质/突触传递和转录/翻译调控在内的10个富集模块。最终，行为分析显示，与B6小鼠相比，BTBR/R小鼠在社会新奇性识别和重复行为上存在轻微但显著的缺陷。此外，BTBR/R数据与先前关于具有ASD的人类受试者和ASD动物模型（包括BTBR/J小鼠）的研究报告进行了全面比较。我们的研究结果使我们能够提出潜在的具有重要意义的基因、ncRNAs和RNA相互作用。对BTBR/R和BTBR/J亚系改变的脑转录组数据的分析有助于理解自闭症易感性的遗传基础。